The etiology of human pulmonary emphysema remains unknown. Recently an enzymatic theory involving proteolysis has been proposed. It is based on two independent observations: one, the finding of a higher than expected incidence of pulmonary emphysema in subjects with a serum deficiency in alpha 1-antitrypsin globulin; the other, the production of similar lesions to those encountered in humans in rats, Syrian hamsters and dogs, using the proteolytic enzyme papain intratracheally. In recent studies in our laboratory we have been able to induce emphysematous lesions in the dog using aerosolized homogenates of dog or human polymorphonuclear leukocytes or dog alveolar macrophages. This proposal includes experiments which will isolate, purify and characterize the factor or factors involved in the production of the observed lesions in animals. It will be determined if there is a multiplicity of factors and if the emphysema inducing agent(s) are lysosomal in origin or localized in another cellular compartment. The effect of various types of proteinase inhibitors on the ability of the factor(s) to produce emphysema will be examined. The possibility that certain lung-specific hydrolases are activated by the aerosolized homogenates will be studied as well as a determination of whether induction of increased levels of macrophage proteinases increases the ability of that cell type to produce emphysematous lesions in the dog. We will determine if the proteinase levels in human polymorphonuclear leukocytes vary between normal subjects (smokers vs. non-smokers) and patients with emphysema or bronchitis and if extracts from one class of these subjects is more effective in producing lung destruction. The sequence of events in the development of experimental emphysema will be monitored by electron microscopy using both in vivo and in vitro induction systems. A number of physiological parameters will be analyzed in order to determine those measurements most useful in correlating with the morphologic changes observed.